The goal of this research proposal is to determine the role of IDO (indolamine 2,3-dioxygenase) in the pathogenesis/host response to infection by Venezuelan equine encephalitis (VEEV) and eastern equine encephalitis (EEEV) viruses. These viruses, particularly VEEV, were developed as biological weapons by the United States Military and former USSR during the cold war and are potential bioterrorist threats due to their ease of transmission and infectivity by the aerosol route. The neuropathogenesis of these viruses and the host response of the central nervous system are still not completely understood. These viruses can cause death and long term sequelae in those that survive. Eastern equine encephalitis is partially virulent with a mortality of more than 50% in those with symptomatic disease. Through this study we hope to discover new ways in which the host's central nervous system reacts to infection from these viruses. If we can better understand the role IDO plays in this process we may be able to develop therapeutics to alleviate disease. Currently the only treatment available for these viruses is symptomatic and supportive therapy. The potential for these viruses to be used as bioweapons and their easy aerosol transmission makes the search for directed therapies of great importance. Dr. Seymour has the necessary skills to carry this project forward while at the same time acquiring new skills and improving his current skills. He will spend 9-person months on this project. The remainder of his time will be devoted to other research projects including work with vaccine candidates against chikungunya, EEEV, VEEV. He will also continue his work on elucidating the role of T-cells in chikungunya infection and his work concerning the pathogenesis of O'nyong-nyong virus. His other activities will include functioning as an attending of the autopsy service for 1 month per year and he will be involved in teaching medical and graduate students. He will have the opportunity to interact with other faculty members during seminars, journal clubs and colloquiums. He will also participate in the department of pathology pre-proposal presentation program for faculty members, which allows them to present their ideas before other faculty members in the department to garner feedback and advice in making their proposal stronger. UTMB recently developed the Academy of Research Mentors and this academy will provide Dr. Seymour with an independent mentor with interests complementary to Dr. Weaver's. He will meet regularly with Dr. Weaver and Dr. Aronson to discuss his progress and ongoing research activities. He will be expected to present his work at the weekly pathology seminar. In addition, he will present his work at least two national or international meetings per year. He will participate in seminars and classes which will focus on the responsible conduct of research, grant writing and among others. During his final two years on this award he will begin to apply for his own independent funding. His immediate goal is to pursue a tenor track position and develop his skill set which will allow him to reach hi long term goal of becoming a successful independent physician-scientist in arboviral immunology and arboviral vaccine development/treatment. The rich research environment at UTMB with numerous successful investigators in arbovirology and other disciplines give him a unique and supportive environment to reach his goals.